Stereoisomers of fatty acid analogs for diagnostic imaging

ABSTRACT

The present invention provides novel imaging agents for clinical diagnosis of injuries and diseases, in the form of a radionuclide in spatial proximity to a substantially pure stereoisomer of a fatty acid analog. The invention also provides methods for using the novel imaging agents, and kits containing one or more of the novel imaging agents of the invention.

This is a request for filing a continuation application under 37 CFR1.53(b), of pending prior application Ser. No. 09/077,490 filed on May29, 1998, of David R. ELMALEH entitled Stereoisomers of Fatty AcidAnalogs for Diagnostic Imaging which in turn claims priority toPCT/US96/19024, filed Nov. 25, 1996, and U.S. Providional ApplicationNo. 60/007,863, filed Dec. 1, 1995.

This invention was made with Government support from the NationalInstitutes of Health. The Government has certain rights in theinvention.

The present invention relates to the field of nuclear medicine. Morespecifically, the invention relates to diagnostic imaging usingsubstantially pure stereoisomers of radionuclide-containing fatty acidanalogs.

BACKGROUND OF THE INVENTION

Clinical imaging technology plays a significant role in diagnosis ofinjuries and disease processes. Virtually any part of an animal's bodycan now be examined for diagnostic purposes using a variety of imagingtechniques. Radiography has long been used to image body parts throughwhich externally generated x-rays are transmitted. Computerized axialtomography (CAT) provides cross-sectional x-ray images of a plane of thebody. Specific tissues or organs may be targeted in positron emissiontomography (PET), single photon emission computed tomography (SPECT),and scintigraphy. In PET, SPECT, and scintigraphy, radiopharmaceuticalagents capable of sequestering to some degree in the target tissue ororgan are internally administered to the patient, and images aregenerated by detecting the radioactive emissions from the sequesteredradiopharmaceutical agent. Radiopharmaceutical agents include nuclidessuch as ²⁰¹Tl, ^(99m)Tc, ¹³³Xe, and the like; chelates of nuclides;nuclide labeled metabolic agents such as ¹¹C-deoxy-D-glucose,¹⁸F-2-fluorodeoxy-D-glucose, [1-¹¹C]- and [¹²³I]-β-methyl fatty acidanalogs, ¹³N-ammonia, and the like; infarct avid agents such as^(99m)Tc-tetracycline, ^(99m)Tc-pyrophosphate, ²⁰³Hg-mercurials,⁶⁷Ga-citrate, and the like; and nuclide labeled monoclonal antibodies.Whole cells such as erythrocytes and leukocytes may also be labeled witha radionuclide and function as radiopharmaceutical agents.

The amount and type of clinical information that can be derived fromPET, SPECT, and scintigraphic images is related in part to the abilityof the radiopharmaceutical agent to sequester in the target tissue ororgan. Although many radiopharmaceuticals are available for clinicaluse, for a given imaging instrument, the agents generally havelimitations in the resolution of the image generated. The resolutionavailable for a particular imaging agent is highly dependent on theaffinity of the radiopharmaceutical to bind at the site of injury ascompared to the affinity of the radiopharmaceutical to bind to healthytissue surrounding the site of injury.

In spite of their limitations, radiopharmaceuticals are used in avariety of types of studies to obtain different kinds of information.For example, radiopharmaceutical agents used in cardiac blood flow andblood pool studies provide information on murmurs, cyanotic heartdisease, and ischemic heart disease. Perfusion scintigraphy agentsprovide measurements of blood flow useful in detection of coronaryartery disease, assessment of pathology after coronary arteriography,pre- and postoperative assessment of coronary artery disease, anddetection of acute myocardial infarction. Infarct avid agents are usedfor “hot spot” infarct imaging. Radiopharmaceuticals which allow bindingto specific cardiac receptors, while generally still in thedevelopmental stage, may allow detection of highly specific binding inthe cardiovascular system. Radionuclide-containing antibodies directedagainst the heavy chain of cardiac myosin have been proposed to identifyzones of acute myocardial necrosis, and ^(99m)Tc-labeled low densitylipoprotein may be useful to detect atheromatous lesions in their earlystages after onset of endothelial damage. ^(99m)Tc-HMPO and¹²³I-iodoamphetamines are used to study changes in brain blood flow withSPECT. Receptor-ligand interactions, glucose utilization, proteinsynthesis, and other physiological parameters are also studied withother radiopharmaceuticals using PET.

Radiopharmaceutical agents capable of detecting the rate and amount ofmetabolism are particularly important to the progress of clinicalnuclear medicine, since they allow studies of the energy consumption inthe various stages of disease processes. For example, cardiac metabolismcan now be studied using labeled physiologic tracers and using analogsof “natural” metabolites that are transported in the same manner as themetabolite but go through only a few reactions of the metabolic pathwayand are then trapped in the tissue in a chemically known form. Theglucose analog [¹⁸F]-2-fluoro-2-deoxy-D-glucose can be used to detectareas of altered glucose metabolism in the heart or other target organswhich may be associated with hypoxia and anoxia and thus aid in definingthe extent of an ischemic injury or cardiomyopathy. Fatty acids are themain source of energy for the heart, and radiolabeled fatty acids ortheir close analogs have been used to study heart metabolic integrity.β-methyl-fatty acid analogs are one group of fatty acids used asmetabolic tracers.

Racemic mixtures of many β-methyl-fatty acid analogs are disclosed inU.S. Pat. No. 4,524,059. One β-methyl-fatty acid analog,[¹²³I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid ([¹²³I]-BMIPP)has been used for myocardial imaging in Japan. However, the racemicnature of [¹²³I]-BMIPP makes it less than optimal for imaging studies,since uptake and metabolism of the R and S stereoisomers may differ andthus decrease the specificity of the reagent for heart tissue. Althoughuse of stereoisomers of β-methyl-fatty acid analogs has been suggested,obtaining such isomers at a meaningful level of purity has beendifficult.

Because an accurate imaging diagnosis of injury or disease depends soheavily on the agent used, a need continues to exist forradiopharmaceuticals with improved tissue and organ specificity.

SUMMARY OF THE INVENTION

The present invention provides improved and novel radiopharmaceuticalagents for diagnostic imaging of injuries and disease states. Theimaging agents of the invention are radionuclide-containing analogs offatty acids and are particularly suitable for cardiovascular and brainimaging. The imaging agents of the invention are substantially purestereoisomers of fatty acid analogs.

In one embodiment, the invention provides an imaging agent comprising aradionuclide in spatial proximity to a stereoisomer of more than 75%isomeric purity of a fatty acid analog having the formula

wherein R₁ is selected from the group consisting of a hydrogen,fluorine, an iodoaryl group, an iodoallyl group, and an iodothiophenegroup; R₂ is selected from the group consisting of a hydrogen, a primaryamine, a secondary amine, a tertiary amine, an alkyl group, asubstituted alkyl group, an aryl group, and a substituted aryl group; R₃is selected from the group consisting of a hydrogen, a methyl, ahydroxyl, a keto ester, a methoxy, a halide, and an amine; and n isgreater than 12.

In another embodiment, the invention provides an imaging agentcomprising a radionuclide in spatial proximity to an isomer of a fattyacid analog having the formula

wherein R₁ is selected from the group consisting of a hydrogen,fluorine, an aryl group, a substituted aryl group, an allyl group, asubstituted allyl group, a vinyl group, a substituted vinyl group, andan iodothiophene group; R₂ is selected from the group consisting of ahydrogen, a primary amine, a secondary amine, a tertiary amine, an alkylgroup, a substituted alkyl group, an aryl group, and a substituted arylgroup; A is selected from the group consisting of a methylene group, anethylene group, an oxygen, a sulfur, and a nitrogen; and n is greaterthan 10.

In another embodiment, the invention provides an imaging agentcomprising a radionuclide in spatial proximity to a stereoisomer of afatty acid analog having the formula

wherein R₁ is selected from the group consisting of a hydrogen,fluorine, an aryl group, a substituted aryl group, an allyl group, asubstituted allyl group, a vinyl group, a substituted vinyl group, andan iodothiophene group; R₂ is selected from the group consisting of ahydrogen, a primary amine, a secondary amine, a tertiary amine, an alkylgroup, a substituted alkyl group, an aryl group, and a substituted arylgroup; R₃ is selected from the group consisting of a hydrogen, a methyl,a hydroxyl, a keto ester, a methoxy, a halide, and an amine; A isselected from the group consisting of a hydrogen, an alkyl group, and ahalide; B is selected from the group consisting of a hydrogen, an alkylgroup, and a halide; n is greater than 3; and m is greater than 3.

In another embodiment, the invention provides a method of imagingcardiovascular or brain tissue in a mammal which comprises administeringto the mammal an imaging agent comprising a radionuclide in spatialproximity to an isomer of a fatty acid analog, and detecting the spatialdistribution of the agent accumulated in the mammal.

In another embodiment, the invention provides a method of detecting acardiovascular lesion in a mammal which comprises administering to themammal an imaging agent comprising a radionuclide in spatial proximityto an isomer of a fatty acid analog, and detecting the spatialdistribution of the agent accumulated in the mammal's cardiovascularsystem, wherein a detected accumulation of agent in a region which isdifferent from the detected accumulation of agent in other regions isindicative of a lesion.

In another embodiment, the invention provides a method of detecting abrain lesion in a mammal which comprises administering to the mammal animaging agent comprising a radionuclide in spatial proximity to anisomer of a fatty acid analog, and detecting the spatial distribution ofthe agent accumulated in the mammal's brain, wherein a detectedaccumulation of agent in a region which is different from the detectedaccumulation of agent in other regions is indicative of a lesion.

In another embodiment, the invention provides a kit for imaging whichcomprises at least one imaging agent comprising a radionuclide inspatial proximity to an isomer of a fatty acid analog, and apharmaceutically acceptable carrier.

In another embodiment, the invention provides a kit for imaging whichcomprises at least one stereoisomer of a fatty acid analog incombination with a chelating agent, and a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. The issuedU.S. patents and allowed applications cited herein are herebyincorporated by reference.

The present invention provides imaging agents which generally comprise aradionuclide in spatial proximity to a substantially pure stereoisomerof a fatty acid analog. In accordance with the invention, spatialproximity between the nuclide and the stereoisomer may be effected inany manner which preserves the specificity of the stereoisomer for itstarget tissue. For example, spatial proximity between the nuclide andthe stereoisomer may be effected by a covalent or non-covalent chemicalbond. Such a chemical bond may be affected through a chelating substanceor an auxiliary molecule. Alternatively, spatial proximity between thenuclide and the stereoisomer may be effected by incorporating thenuclide and the stereoisomer in a micelle or liposome, in such a waythat the affinity of the stereoisomer for its target tissue ismaintained. Spatial proximity between the nuclide and the stereoisomermay also be effected by attaching the nuclide and the stereoisomer to amatrix such as a microsphere.

As defined herein a “substantially” pure stereoisomer is one containingmore than 75% of a single stereoisomer of fatty acid analog. Preferably,the substantially pure stereoisomer of the invention contains more than75% of a single stereoisomer of a fatty acid analog. More preferably,the substantially pure stereoisomer of the invention contains more than80% of a single stereoisomer of a fatty acid analog. Most preferably,the substantially pure stereoisomer of the invention contains more than85% of a single stereoisomer of a fatty acid analog.

In one embodiment, the imaging agent of the invention comprises aradionuclide in spatial proximity to a stereoisomer of more than 75%isomeric purity of a β-methyl (or 2-methyl) fatty acid analog having theformula

wherein R₁ is selected from the group consisting of a hydrogen,fluorine, an iodoaryl group, an iodoallyl group, and an iodothiophenegroup; R₂ is selected from the group consisting of a hydrogen, a primaryamine, a secondary amine, a tertiary amine, an alkyl group, asubstituted alkyl group, an aryl group, and a substituted aryl group; R₃is selected from the group consisting of a hydrogen, a methyl, ahydroxyl, a keto ester, a methoxy, a halide, and an amine and n isgreater than 12. In this embodiment, the stereoisomer may be anR-stereoisomer or an S-stereoisomer. This embodiment encompassesstereoisomers having the formula as shown, where R₃ is bonded at the C3position as shown, and in addition encompasses aliphatic fatty acidanalogs having similar formulae but in which R₃ is bonded to othercarbon moieties of the fatty acid chain. For example, R₃ may be bondedat the C5, C7, or C9 position of the aliphatic fatty acid chain,counting from the carboxyl carbon. Racemic mixtures of such fatty acidanalogs are disclosed in U.S. Pat. No. 4,524,059.

Stereoisomers of β-methyl fatty acid analogs having greater than 75%purity as defined above may be prepared using any of the syntheticschemes set forth below. In general, the stereoisomers of the inventionmay be prepared using an asymmetric synthesis combined with finalchromatographic separation on an optically active support or anoptically active element, as indicated in Schemes 1 and 2.Alternatively, stereoisomers of the starting materials may be separatedusing known methods, and synthesis of the stereoisomer of the inventionmay be completed without changing the configuration of the opticallyactive moiety. All precursors, intermediates, and final products of thesyntheses may optionally be subjected to additional asymmetricchromatographic separations, to increase the stereoisometric purity ofthe fatty acid analog.

An Asymetric Synthesis of an R-3-methylfatty acid

The final optically active product could be further enriched byasymetric chromatographic methods.

An Asymetric Synthesis of an S-3-methylfatty Acid

The final optically active product could be further enriched byasymetric chromatographic methods.

LDA=lithium diisopropyl amido THF=tetrahydrofuran

An Alternative Synthesis for R or S 3-methyl Substituted Fatty Acids

In this scheme the synthesis and separation of the optical isomers ofprecursor 1 is performed prior to the chemical synthesis of the finalfatty acid 2. The optical isomers of 2 could be further enriched byasymetric chromatographic methods.

The invention is also embodied as an imaging agent comprising aradionuclide in spatial proximity to a stereoisomer of an α,β-substituted (or 2,3-substituted) fatty acid analog having the formula

wherein R₁ is selected from the group consisting of a hydrogen, afluorine, an iodoaryl group, an iodoallyl group and an iodothiophenegroup; R₂ is selected from the group consisting of a hydrogen, a primaryamine, a secondary amine, a tertiary amine, an alkyl group, asubstituted alkyl group, an aryl group, and a substituted aryl group; R₄is an alkyl group; R₅ is an alkyl group; and n is greater than 12. Inthis embodiment, the imaging agent may be a 2S,3S-stereoisomer, a2S,3R-stereoisomer, a 2R, 3R-stereoisomer, or a 2R,3S-stereoisomer.Stereoisomers of α, β-substituted fatty acid analogs having greater than75% purity as defined above may be prepared using modifications ofsynthetic schemes 1–3, wherein a hydrogen of the α-carbon is substitutedwith an R₄ moiety.

The invention may also be embodied as an imaging agent comprising aradionuclide in spatial proximity to an isomer of a fatty acid analoghaving the formula

wherein R₁ is selected from the group consisting of a hydrogen, afluorine, an aryl group, a substituted aryl group, an allyl group, asubstituted allyl group, a vinyl group, a substituted vinyl group, andan iodothiophene group; R₂ is selected from the group consisting of ahydrogen, a primary amine, a secondary amine, a tertiary amine, an alkylgroup, a substituted alkyl group, an aryl group, and a substituted arylgroup; A is selected from the group consisting of a methylene group, anethylene group, an oxygen, a sulfur, and a nitrogen; and n is greaterthan 10. The imaging agent of this embodiment may be prepared accordingto the synthetic scheme set forth below.

Synthesis of Oxiranyl Fatty Acids

The invention is further embodied as an imaging agent comprising aradionuclide in spatial proximity to a stereoisomer of a fatty acidanalog having the formula

wherein R₁ is selected from the group consisting of a hydrogen, afluorine, an aryl group, a substituted aryl group, an allyl group, asubstituted allyl group, a vinyl group, a substituted vinyl group, andan iodothiophene group; R₂ is selected from the group consisting of ahydrogen, a primary amine, a secondary amine, a tertiary amine, an alkylgroup, a substituted alkyl group, an aryl group, and a substituted arylgroup; R₃ is selected from the group consisting of a hydrogen, a methyl,a hydroxyl, a keto ester, a methoxy, a halide, and an amine; A isselected from the group consisting of a hydrogen, an alkyl group, and ahalide; B is selected from the group consisting of a hydrogen, an alkylgroup, and a halide; n is greater than 3; and m is greater than 3. Inthis embodiment, the stereoisomer may be an R, cis-stereoisomer, an R,trans-stereoisomer, an S, cis-stereoisomer, or an S, trans-stereoisomer.Stereoisomers having greater than 75% purity as defined above may beprepared using the synthetic scheme set forth below.

Synthesis of Monounsaturated Fatty Acids

The imaging agents described above may contain any radionuclide inaccordance with the invention. Preferably, the imaging agents of theinvention contain radionuclides suitable for use in PET or SPECTimaging. More preferably, the imaging agent of the invention contains aradionuclide selected from the group consisting of ¹²³I, ^(99m)Tc, ¹⁸F,⁶⁸Ga, ⁶²Cu, ¹¹¹In, and the like. Such radionuclides may be incorporatedinto the imaging agent by covalent bonding directly to an atom of thefatty acid moiety, or the radionuclide may be non-covalently orcovalently associated with the fatty acid moiety through a chelatingstructure. Any suitable chelating structure may be used to provide thecovalent or non-covalent association between the radionuclide and thefatty acid moiety of the agent. Many such chelating structures are knownin the art. Preferably, the chelating structure is selected from thegroup consisting of an N₂S₂ structure, an N₄ structure, an isonitrile, ahydrazine, a HYNIC (hydrazinonicotinic acid) group, a phosphoruscontaining group, and the like. The chelating structure may becovalently or non-covalently associated with any moiety of the imagingagent. For example, the chelating structure may be associated with theR₁ moiety of the fatty acid analog, with the R₂ moiety of the fatty acidanalog, or with the (CH₂)_(n) moiety of the analog. In accordance withthe invention, the stereoisomer of the fatty acid analog may besynthesized to contain a chelating group, or a chelating group may beadded to the stereoisomer after synthesis.

When ¹²³I is the radionuclide, the fatty acid analog stereoisomer may belabeled in accordance with the general radioiodination protocol setforth below.

General Radioiodination Procedures

Other methods for radioiodinating the stereoisomer may also be used, forexample, Bolton-Hunter radioiodination, chloramine T radioiodination,and the like.

When the radionuclide is ^(99m)Tc, the imaging agent may be labeledaccording to the general labeling protocol set forth below.

^(99m)Tc-Radiolabeling of Fatty Acids

Other N₂S₂ fatty acid configurations are possible e.g.

The cardiovascular imaging agents of the invention may be used inaccordance with the methods of the invention by those of skill in theart, e.g., by specialists in nuclear medicine, to image cardiovascularor brain tissue in a mammal or to detect cardiovascular or brain lesionsin a mammal. Some cardiovascular or brain lesions are evident when adark spot appears within the image, for example, within a labeled heartor within a labeled brain, indicating the presence of necrotic tissue.Alternatively, a carcinomic lesion might be detectable as a brighterspot within the image, indicating a region of enhanced metabolism at thesite of a tumor. A particularly useful imaging approach employs morethan one imaging agent to perform simultaneous studies. For example,simultaneous studies of perfusion and metabolic function would allowstudy of coupling and uncoupling of flow and metabolism, thusfacilitating determinations of tissue viability after a cardiac injury.Such determinations are useful in diagnosis of cardiac ischemia,cardiomyopathy, tissue viability, hybrinating heart, and other heartabnormalities.

The imaging agents of the invention are used in the following manner. Aneffective amount of the imaging agent (from 1 to 50 mCi) may be combinedwith a pharmaceutically acceptable carrier for use in imaging studies.In accordance with the invention, “an effective amount” of the imagingagent of the invention is defined as an amount sufficient to yield anacceptable image using equipment which is available for clinical use. Aneffective amount of the imaging agent of the invention may beadministered in more than one injection. Effective amounts of theimaging agent of the invention will vary according to factors such asthe degree of susceptibility of the individual, the age, sex, and weightof the individual, idiosyncratic responses of the individual anddosimetry. Effective amounts of the imaging agent of the invention willalso vary according to instrument and film-related factors. Optimizationof such factors is well within the level of skill in the art.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic agents, absorption delaying agents, and the like. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The imaging agent of the invention may further beadministered to an individual in an appropriate diluent or adjuvant,co-administered with enzyme inhibitors or in an appropriate carrier suchas human serum albumin or liposomes. Supplementary active compounds canalso be incorporated into the imaging agent of the invention.Pharmaceutically acceptable diluents include saline and aqueous buffersolutions. Adjuvants contemplated herein include resorcinols, non-ionicsurfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether. Enzyme inhibitors include pancreatic trypsininhibitor, diethylpyrocarbonate, and trasylol. Liposomes includewater-in-oil-in-water CGF emulsions as well as conventional liposomes(Strejan et al. (1984) J. Neuroimmunol. 7, 27).

Preferably, the imaging agent of the invention is administeredintravenously, and the imaging agent will be formulated as a sterile,pyrogen-free, parenterally acceptable aqueous solution. The preparationof such parenterally acceptable solutions, having due regard to pH,isotonicity, stability, and the like, is within the skill in the art. Apreferred formulation for injection should contain, in addition to thecardiovascular imaging agent, an isotonic vehicle such as SodiumChloride Injection, Ringer's Injection, Dextrose Injection, Dextrose andSodium Chloride Injection, Lactated Ringer's Injection, or other vehicleas known in the art. The formulation used in the present invention mayalso contain stabilizers, preservatives, buffers, antioxidants, or otheradditives known to those of skill in the art.

The amount of imaging agent used for diagnostic purposes and theduration of the imaging study will depend upon the nature and severityof the condition being treated, on the nature of therapeutic treatmentswhich the patient has undergone, and on the idiosyncratic responses ofthe patient. Ultimately, the attending physician will decide the amountof imaging agent to administer to each individual patient and theduration of the imaging study.

In another embodiment, the invention provides a kit for imaging whichcomprises one or more of the imaging agents described above, incombination with a pharmaceutically acceptable solution containing acarrier such as human serum albumin or an auxiliary molecule such asmannitol or gluconate. Human serum albumin for use in the kit of theinvention may be made in any way, for example, through purification ofthe protein from human serum or through recombinant expression of avector containing a gene encoding human serum albumin. Other substancesmay also be used as carriers in accordance with this embodiment of theinvention, for example, detergents, dilute alcohols, carbohydrates, andthe like. In one embodiment, a kit according to the invention maycontain from about 1 to about 30 mCi of an imaging agent. In anotherembodiment, a kit may contain the unlabeled fatty acid stereoisomerwhich has been covalently or non-covalently combined with a chelatingagent, and an auxiliary molecule such as mannitol, gluconate, and thelike. The unlabeled fatty acid stereoisomer/chelating agent may beprovided in solution or in lyophilized form. The radionuclide, forexample, ^(99m)Tc from a commercially available ⁹⁹Mo/^(99m)Tc generator,is combined with the unlabeled fatty acid stereoisomer/chelating agentfor a time and at a temperature sufficient to chelate the radionuclideto the fatty acid stereoisomer/chelating agent, and the imaging agentthus formed is injected into the patient. The kits of the invention mayalso include other components which facilitate practice of the methodsof the invention. For example, buffers, syringes, film, instructions,and the like may optionally be included as components of the kits of theinvention.

Although a few exemplary embodiments of this invention have beendescribed in detail above, those skilled in the art will readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. For example, many other chemical groupsare interchangeable with the various substituted moieties withoutsignificantly altering the activity of the stereoisometric fatty acidanalog for diagnostic imaging purposes. Accordingly, all suchmodifications are intended to be included within the scope of thisinvention as defined in the following claims.

1. A method of radio imaging cardiovascular tissue of a subjectcomprising administering intravenously to a subject an effective amountof pharmaceutical composition comprising: (i) an imaging agent includinga substantially pure stereoisomer of a radionuclide labeled β-methylfatty acid analog having a formula,R₁(CH₂)_(n)C(R₃)HCH₂COOR₂  in which R₁ is selected from the groupconsisting of hydrogen, fluorine, an aryl group, a substituted arylgroup and an iodothiophene group; R₂ is selected from the groupconsisting of a hydrogen, a primary amine, a secondary amine, a tertiaryamine, an allyl group, a substituted alkyl group, an aryl group, and asubstituted aryl group; R₃ is selected from the group consisting of ahydrogen, a methyl, a hydroxyl, a keto ester, a methoxy, a halide, andan amine and n is greater than or equal to 12; and (ii) a chelatingstructure.
 2. The method of claim 1 in which the chelating structure iscovalently or noncovalently associated with any moiety of the imagingagent.
 3. The method of claim 1 in which R₁ of the formula comprises ap-radiohalophenyl group.
 4. The method of claim 3 in which thep-radiohalophenyl group is selected from the group consisting ofp-radioiodophenyl and p-radiofluorophenyl.
 5. The method of claim 1 inwhich the radionuclide labeled β-methyl fatty acid analog is15-(p-[¹²³I]iodophenyl)-3-(R)-methylpentadecanoic acid.
 6. The method ofclaim 1 in which the radionuclide labeled β-methyl fatty acid analog is15-(p-[¹²³I]iodophenyl)-3-(S)-methylpentadecanoic acid.
 7. The method ofclaim 1 in which the radionuclide labeled β-methyl fatty acid analog is15-(p-[¹⁸F]fluorophenyl)-3-(R)-methylpentadecanoic acid.
 8. The methodof claim 1 in which the radionuclide labeled β-methyl fatty acid analogis 15-(p-[¹⁸F]fluorophenyl)-3-(S)-methylpentadecanoic acid.
 9. Themethod of claim 1 in which the radionuclide labeled β-methyl fatty acidanalog is 15-(p-[¹³¹I]iodophenyl)-3-methylpentadecanoic acid.
 10. Themethod of claim 9 in which the radionuclide labeled β-methyl fatty acidhas an (R)-stereoisomeric configuration.
 11. The method of claim 9 inwhich the radionuclide labeled β-methyl fatty acid has an(S)-stereoisomeric configuration.